Mesothelioma is a tumor that occurs in the mesothelium that covers the surface of the pleura, peritoneum and pericardium that respectively envelop the organs of the chest cavity such as the lungs and heart, and abdominal organs such as the digestive tract and liver. In the case of diffuse pleural mesothelioma, chest pain is caused by invasion of the intercostal nerves on the side of the chest wall pleura, and respiratory and circulatory disorders may occur due to tumor growth and accumulation of pleural fluid in the pleura on the organ side (Takagi, Journal of Clinical and Experimental Medicine, (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999). Eventually, there is proliferation into the adjacent mediastinal organs, progressing to direct invasion of the heart or development in the abdominal cavity by means of the diaphragm, or there may be development outside the chest cavity as a result of additional lymphatic or circulatory metastasis.
In the U.S., diffuse pleural mesothelioma is reported to occur in 3,000 persons annually, with the number of cases increasing significantly through the 1980's. The disease is frequently observed in men in their sixties, with the incidence in men being roughly five times that in women. According to recent reports in the U.S. and Europe, the incidence of mesothelioma demonstrates a rapidly increasing trend, and, based on epidemiological statistics from the U.K. in 1995, the number of deaths from mesothelioma is predicted to continue to increase over the next 25 years. In the worst possible scenario, mesothelioma may be found to account for 1% of all deaths among men born in the 1940's.
Numerous different classification schemes for the clinical disease stages have been established for mesothelioma, and since the classification methods differ, comparison of the results of treatment for mesothelioma is difficult (Nakano, Environ Health Prev Med, 2008; 13:75-83).
In addition, malignant mesothelioma (MM) has a causative relationship with exposure to asbestos, and this has also been demonstrated in animal experiments (Tada, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 406-408, 1999). Asbestos that has been inhaled into the respiratory tract reaches a location directly beneath the pleura where a tumor eventually develops due to chronic irritation for typically 20 years, and this tumor spreads in a thin layer over the entire surface of the pleura. Consequently, although malignant mesothelioma is classified as an asbestos-related disease, not all malignant mesothelioma is caused by asbestos, and well-documented exposure is only observed in about half of all patients.
Malignant pleural mesothelioma (MPM) is resistant to treatment, is associated with an extremely poor prognosis, and requires that countermeasures be taken immediately (Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999). For example, although the folic acid antagonist, methotrexate (MTX), has a satisfactory efficacy rate of 37% in large-dose single treatment in combination with leucovin, its use has not proliferated due to the technical difficulty associated with application to mesothelioma that causes retention of a large amount of pleural fluid (Nakano, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 570-573, 2003). In addition, although pleuropulmonary excision and pleurectomy are performed for diffuse pleural mesothelioma, there is increased susceptibility to relapse following treatment, and the post-surgical local relapse rate in particular is high at 35-43% (Takagi, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999).
The prognosis for malignant mesothelioma is influenced by the stage of the disease. Surgery, when performed as part of a multimodality therapy with cytotoxic chemotherapy and radiation therapy, as well as adjuvant immunological treatments (e.g., interferon or interleukin) can be an effective treatment, but only in the rare event of diagnosis at an early stage.
The incidence of mesothelioma worldwide is increasing and only a minority of patients can benefit from a surgical resection. For patients who are not amenable to curative resection, median overall survival is around 6-7 months. Therapeutic options are limited. Most patients, either treated or untreated, die of complications from local disease. Marketed chemotherapeutic agents, as a single agent or in combination, did not prove able to significantly impact survival.
In mesothelioma, the 9p21.3 deletions are often homozygous and linked with poor prognosis (Ivanov et al., Int J Cancer 2009; 124:589-599). Two tumor suppressor genes are localized in this area: CDKN2A (cyclin-dependent kinase inhibitor), which encodes the cell cycle inhibitory p16INK4A and p14ARF proteins, and the adjacent CDKN2B (p15.sup.INK4B) (Ruas and Peters, Biochim Biophys Acta 1998; 1378:F115-177). Combined deficiency of these products may have a synergistic effect in malignant transformation (Krimpenfort et al., Nature 2007; 448:943-946).
Much emphasis has been placed on the discovery and characterization of a unique tumor marker. However, no marker has yet been identified that has adequate sensitivity or specificity to be clinically useful, although a combination of multiple markers has been shown to increase prognostic accuracy. There is an unmet need for identification of specific and accurate markers associated with mesothelioma, especially those which could have prognostic significance in determining the type and extent of therapy necessary or reasonable for survival, and for compositions which could be employed in treating mesothelioma.
Therefore, a clinically applicable assay directed to a truly predictive biomarker is needed in order to aid in accurately diagnosing subjects and stratifying the risk faced by those subjects. Such an assay would also assist in identifying the survival prognosis of subjects as well as predicting therapeutic responsiveness to specific therapies and treatments.